ONLINE TDM CARBAMAZEPINE

K031902 · Roche Diagnostics Corp. · KLT · Sep 17, 2003 · Clinical Toxicology

Device Facts

• Record ID: K031902
• Device Name: ONLINE TDM CARBAMAZEPINE
• Applicant: Roche Diagnostics Corp.
• Product Code: KLT · Clinical Toxicology
• Decision Date: Sep 17, 2003
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.3645
• Device Class: Class 2

Indications for Use

The ONLINE TDM Carbamazepine assay is for the quantitative determination of carbamazepine in human serum or plasma on automated clinical chemistry analyzers. This neuroleptic drug assay test system is a device intended to measure in serum or plasma the dopamine receptor blocking activity of carbamazepine. This device is for in vitro diagnostic use, and intended for prescription use.

Device Story

ONLINE TDM Carbamazepine is a homogeneous microparticle agglutination immunoassay (KIMS) for quantitative drug monitoring in human serum or plasma. Input: patient serum/plasma sample. Principle: competitive reaction between biotinylated drug hapten and free carbamazepine in sample for binding sites on anti-carbamazepine antibody and streptavidin-coated latex beads. Output: signal decrease proportional to drug concentration. Used in clinical laboratories on Roche Hitachi 911, 912, 917, and Modular P automated analyzers. Results interpreted by physicians to adjust dosage and maintain therapeutic drug levels, avoiding sub-therapeutic or toxic ranges.

Clinical Evidence

Bench testing only. Method comparison study (n=102) against predicate using Passing-Bablok and linear regression showed slopes of 1.068 and 1.062, respectively (r=0.984). Precision studies (within-run, day-to-day, total) performed over 21 days showed total %CV between 3.6% and 5.6%. Linearity confirmed across reportable range. Matrix comparison (serum vs. various plasmas) showed slopes 0.9-1.1 and r ≥ 0.95. Analytical specificity tested against 40+ compounds.

Technological Characteristics

Homogeneous microparticle agglutination immunoassay (KIMS). Two-reagent system. Components: biotinylated drug hapten, anti-carbamazepine antibody, streptavidin-coated latex beads. Automated clinical chemistry analyzer platform. Quantitative measurement via signal attenuation.

Indications for Use

Indicated for quantitative determination of carbamazepine in human serum or plasma to aid in monitoring drug levels, adjusting dosage, and achieving therapeutic effect while avoiding toxicity. For use on automated clinical chemistry analyzers.

Regulatory Classification

Identification

A neuroleptic drugs radioceptor assay test system is a device intended to measure in serum or plasma the dopamine receptor blocking activity of neuroleptic drugs and their active metabolites. A neuroleptic drug has anti-psychotic action affecting principally psychomotor activity, is generally without hypnotic effects, and is a tranquilizer. Measurements obtained by this device are used to aid in determining whether a patient is taking the prescribed dosage level of such drugs.

Predicate Devices

• COBAS INTEGRA Carbamazepine assay (K951595)

Submission Summary (Full Text)

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510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION
DECISION SUMMARY
DEVICE ONLY TEMPLATE

A. 510(k) Number: K031902
B. Analyte: Carbamazepine
C. Type of Test: Quantitative homogeneous microparticle agglutination immunoassay
D. Applicant: Roche Diagnostics Corporation
E. Proprietary and Established Names: ONLINE TDM Carbamazepine

F. Regulatory Information:
1. Regulation section: 21 CFR § 862.3645
2. Classification: Class II
3. Product Code: KLT
4. Panel: Toxicology (91)

G. Intended Use:
1. Intended use(s):
The ONLINE TDM Carbamazepine assay is for the quantitative determination of carbamazepine in human serum or plasma on automated clinical chemistry analyzers.

2. Indication(s) for use:
The ONLINE TDM Carbamazepine assay is for the quantitative determination of carbamazepine in human serum or plasma on automated clinical chemistry analyzers. This neuroleptic drug assay test system is a device intended to measure in serum or plasma the dopamine receptor blocking activity of carbamazepine.

This device is for in vitro diagnostic use, and intended for prescription use.

3. Special condition for use statement(s):
Not applicable.

4. Special instrument Requirements:
The device is for use on automated clinical chemistry analyzers. Performance was demonstrated in this submission on the Roche Hitachi 917 analyzer and protocols for testing and minimum acceptance criteria were submitted for qualifying the assay on the Roche Hitachi 911, 912 and Modular P analyzers.

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H. Device Description:

The ONLINE TDM Carbamazepine assay is for the quantitative determination of carbamazepine in human serum or plasma on automated clinical chemistry analyzers. It is a homogeneous microparticle agglutination immunoassay based on the kinetic interaction of microparticles (KIMS). Biotinylated drug hapten serves as the binding partner to anti-carbamazepine antibody and streptavidin coated latex beads. A competitive reaction to a limited amount of specific anti-carbamazepine antibody takes place between the hapten and free carbamazepine in the sample. A decrease in the apparent signal produced by the microparticle agglutination is proportional to the amount of drug present in the sample.

I. Substantial Equivalence Information:

1. Predicate device name(s): COBAS INTEGRA Carbamazepine assay
2. Predicate K number(s): K951595
3. Comparison with predicate:

| Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Intended Use | Therapeutic Drug Monitoring of Carbamazepine | Therapeutic Drug Monitoring of Carbamazepine |
| Matrix | Human serum and plasma | Human serum and plasma |
| Calibrators and Controls | COBAS-FP Carbamazepine calibrators and TDM Multianalyte controls | COBAS-FP Carbamazepine calibrators and TDM Multianalyte controls |
| Differences | | |
| Item | Device | Predicate |
| Methodology | Kinetic interaction of microparticles in a solution | Fluorescence Polarization Immunoassay |
| Chemistry Analyzers | Roche Hitachi analyzers | COBAS INTEGRA analyzers |

J. Standard/Guidance Document Referenced (if applicable):

Not applicable.

K. Test Principle:

The ONLINE TDM Carbamazepine assay is for the quantitative determination of carbamazepine in human serum or plasma on automated clinical chemistry analyzers. It is a homogeneous microparticle agglutination immunoassay based on the kinetic interaction of microparticles (KIMS). Biotinylated drug hapten serves as the binding partner to anti-carbamazepine antibody and streptavidin coated latex beads. A competitive reaction to a limited amount of specific anti-carbamazepine antibody takes place between the hapten and free carbamazepine in the sample. A decrease in

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the apparent signal produced by the microparticle agglutination is proportional to the amount of drug present in the sample.

# L. Performance Characteristics (if/when applicable):

# 1. Analytical performance:

# a. Precision/Reproducibility:

Reproducibility was determined in two different experiments using three levels of the COBAS-FP Multianalyte controls and a low and high human serum pool. Within-run imprecision was calculated from 21 determinations of each of the samples. Day to Day imprecision was calculated using one determination of the five samples in one run per day for 21 days. Total imprecision was calculation using three determinations of the five samples in one run per day for 21 days.

| Sample | Within-run | | | Day-to-Day | | | Total | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Mean | SD | %CV | Mean | SD | %CV | Mean | SD | %CV |
| Level I | 2.9 | 0.05 | 1.6 | 2.8 | 0.15 | 5.4 | 2.8 | 0.15 | 5.6 |
| Level II | 8.4 | 0.14 | 1.6 | 8.3 | 0.32 | 3.8 | 8.3 | 0.36 | 4.3 |
| Level III | 14.4 | 0.29 | 2.1 | 14.1 | 0.49 | 3.5 | 14.1 | 0.55 | 3.9 |
| Low | 6.3 | 0.12 | 1.9 | 5.8 | 0.21 | 3.6 | 5.8 | 0.21 | 3.6 |
| High | 12.2 | 0.29 | 2.3 | 12.2 | 0.48 | 3.9 | 12.2 | 0.44 | 3.6 |

# b. Linearity/assay reportable range:

To assess linearity a drug free pool of human serum was spiked to a high concentration and diluted with a pool of drug free serum.

Results were evaluated by linear regression.

| % High Sample | Theoretical Value (ug/mL) | Assayed Value (ug/mL) | % Recovery |
| --- | --- | --- | --- |
| 100 | 27.3 | 31.0 | 113.3 |
| 90 | 24.6 | 27.0 | 109.6 |
| 80 | 21.8 | 23.5 | 107.7 |
| 70 | 19.1 | 19.1 | 100 |
| 60 | 16.3 | 15.7 | 96.0 |
| 50 | 13.6 | 13.6 | 100 |
| 40 | 10.8 | 10.8 | 100 |
| 30 | 8.1 | 7.8 | 96.4 |
| 20 | 5.3 | 5.2 | 97.2 |
| 10 | 2.6 | 2.6 | 100 |

# c. Traceability (controls, calibrators, or method):

Not applicable.

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d. Detection limit:
The lower detection limit is 0.2 ug/mL as determined by the zero calibrator plus 2 standard deviations.

e. Analytical specificity:
The following compounds were tested for cross-reactivity at two different levels of carbamazepine concentrations:

| Compound | Concentration Tested ug/mL | % Cross-reactivity at ≈ 6 ug/mL drug | % Cross-reactivity at ≈ 13 ug/mL drug |
| --- | --- | --- | --- |
| 10-Hydroxycarbamazepine | 100 | 1.2 | 1.6 |
| 5-(p-Hydroxyphenyl)-5-phenyl | 1000 | ND | ND |
| Acetaminophen | 200 | 0.3 | 0.6 |
| Acetyl cysteine | 150 | 0.7 | 2.2 |
| Acetylsalicylic Acid | 1000 | 1.0 | 1.9 |
| Amitriptylene | 100 | 0.2 | 0.3 |
| Amobarbital | 1000 | ND | 0 |
| Ampicillin-Na | 1000 | 1.7 | 0.1 |
| Ascorbic Acid | 300 | 0.3 | 0.6 |
| Carbamazepine-10,11-epoxide | 29.6 | 14.0 | 17.6 |
| Cefoxitin | 2500 | 9.3 | 5.8 |
| Chlordiazepoxide | 30 | ND | ND |
| Clonazepam | 12 | ND | ND |
| Cyclosporine | 5 | 2 | 0.6 |
| Diazepam | 25 | ND | 0.7 |
| Doxycycline (Tetracycline) | 50 | 2.7 | 2.2 |
| Ethosuximide | 1000 | ND | ND |
| Ethotoin | 1000 | ND | ND |
| Glutethimide | 1000 | ND | 0 |
| Ibuprofen | 500 | 0.8 | 0.8 |
| Imipramine | 200 | 0.1 | 0.2 |
| K-Dobesilate | 200 | 1.9 | 0.2 |
| Levodopa | 20 | 1.8 | 0.2 |
| Mephenytoin | 1000 | 0 | ND |
| Methosuximide | 100 | ND | 0.2 |
| Methyldopa + 1,5 | 20 | 1.4 | 0.8 |
| Metronidazole | 200 | 1 | 1.1 |
| Nortriptylene | 50 | 0.5 | 0.8 |
| Oxacarbazepine | 100 | 1.0 | 1.4 |
| Phenobarbital | 1000 | ND | ND |
| Phenothiazine | 200 | 0.1 | 0.2 |
| Phenylbutazone | 400 | 2.2 | 3.4 |
| Phenytoin | 1000 | 0 | 0 |

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| Compound | Concentration Tested ug/mL | % Cross-reactivity at ≈ 6 ug/mL drug | % Cross-reactivity at ≈ 13 ug/mL drug |
| --- | --- | --- | --- |
| p-Hydroxyphenobarbital | 100 | ND | 0.2 |
| Primidone | 1000 | ND | 0 |
| Probenecid | 500 | ND | 0.1 |
| Promethazine | 1000 | 0 | 0.1 |
| Rifampicin | 60 | 1 | 3.1 |
| Secobarbital | 1000 | ND | 0 |
| Theophylline | 100 | 1.4 | 1.6 |

f. Assay cut-off:
Not Applicable

2. Comparison studies:

a. Method comparison with predicate device:
A total of 102 non-pooled human serum samples were tested with the ONLINE TDM Carbamazepine assay on a Roche Hitachi 917 analyzer and with the COBAS-FP Carbamazepine assay on an Integra 700 analyzer. A comparison of the data from the two assays with Passing-Bablok regression and linear regression analyses gave best fits with slopes of 1.068 and 1.062, respectively, and y intercepts of -0.20 and -0.17, respectively (r = 0.984 for both). Sample concentrations were between 0.5 and 11.93 ug/mL.

b. Matrix comparison:
Comparison of results obtained with human serum and lithium heparin plasma, sodium heparin plasma, EDTA K2 plasma and EDTA K3 plasma were performed. All Passing-Bablok regression analyses have slopes between 0.9 and 1.1 and correlation coefficient r ≥ 0.95.

3. Clinical studies:

a. Clinical sensitivity:
Not Applicable

b. Clinical specificity:
Not Applicable

c. Other clinical supportive data (when a and b are not applicable):
Not Applicable

4. Clinical cut-off:
Not Applicable

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5. Expected values/Reference range: Not Applicable

M. Conclusion:

Based upon the information provided, I recommend that the ONLINE TDM Carbamazepine assay be found substantially equivalent to predicate devices according to 21 CFR § 862.3645.